Although the incidence of endometrial cancer in African-American (AA) women is lower than in Caucasian (C) women, a striking racial disparity exists in endometrial cancer survival rates in the United States, with blacks having up to 30% worse survival rates than whites. Socio-demographic factors alone cannot account for this difference because differences in survival still occur when analyses are adjusted for black and white women by stage and by biologically aggressive (i.e., Type II) endometrial tumors. Uterine serous papillary carcinoma (USC), represents the most aggressive histologic subtype of endometrial cancer. This variant of endometrial carcinoma is up to three fold more frequent in AA women when compared to C women. On the basis of our recently published data on the genetic landscape of USC suggesting that genetic and biologic factors may underlie the racial disparity in survival rates and with the ultimate goal to develop novel, more specific and more effective treatment modalities for the diagnosis and therapy of USC so common in AA women, we propose the following: Aim 1: Identify through whole exome sequencing driver mutation candidates, loss of heterozygosity (LOH) patterns and copy number variations (CNV) in 200 USC samples and use bioinformatics strategies to perform a systematic assessment of genetic differences between AA vs C tumors, Aim 2: Evaluate miRNAs and mRNA expression differences in USC from AA and C and perform downstream analysis of pathways influencing disease in different groups of USC (i.e., c-erbB2+ vs negative and PIK3CA and CCNE1 mutants vs wild type) and Aim 3: Evaluate the biochemical properties of a subset of novel PIK3CA mutations and validate the c-erbB2/PIK3CA and CCNE1 pathways as novel targets for USC treatment using primary USC cell lines and targeted agents including trastuzumab and T-DM1 (i.e., mAbs targeting c-erbB2), AZD8055, GDC-0980 and CYC065 (i.e., a mTOR/PI3K/CDK inhibitors) in in vitro and in vivo assays. This proposal encompasses the first integrated analysis of genomic differences in USC developed by AA when compared to C women as well as the validation of the currently identified differentially expressed genes harboring key driver mutations as novel targets for USC therapy in minority. Relevance Definition and functional validation of key driver mutations and downstream signaling pathways differentially active in AA women harboring USC may be used to guide novel, highly effective targeted therapies against these highly aggressive tumors and, therefore, may have immediate clinical relevance on minority health.